Research into mutations in the gene encoding the epidermal growth factor receptor protein has revolutionized non–small cell lung cancer treatment in recent years, yet the science supporting targeting of this oncogene is still being elucidated.
Research into mutations in the gene encoding the epidermal growth factor receptor (EGFR) protein has revolutionized non–small cell lung cancer (NSCLC) treatment in recent years, yet the science supporting targeting of this oncogene is still being elucidated.
“It’s such a natural part of management for advanced lung cancer now,” Stephen Liu, MD, associate professor of medicine, director of thoracic oncology, and director of developmental therapeutics at the Lombardi Comprehensive Cancer Center of Georgetown University, in Washington, DC, said in an interview with Targeted Therapies in Oncology. “It’s easy to forget it wasn’t that long ago that we didn’t really understand how these alterations impacted the treatment of cancer.”
Ever since EGFR overexpression on the surface of malignant cells was first identified in patients with lung cancer, investigators have been working to determine how best to leverage that insight. “We saw that if you had one of these mutations within EGFR, your tumor was exquisitely sensitive to these EGFR kinase inhibitors,” Liu said.
That realization prompted a wave of new research, including a meta-analysis showing that about one-third of patients with NSCLC harbor an EGFR mutation.1 Insights into the molecular underpinnings of NSCLC can help identify subsets of patients who have different prognoses and are likely to benefit from specific types of treatment. Over the past several years, investigators have capitalized on this expanding knowledge base to foster dramatic results, but they are also chasing a moving target. Resistance to earlier tyrosine kinase inhibitors (TKIs) is growing, and the molecular heterogeneity of NSCLC is prompting investigators to explore a wide range of treatment combinations and strategies to more precisely tailor treatments to individual patients.
Of late, some investigators have shifted their focus from from targeted treatment options to how an EGFR mutation affects the course of a patient’s disease. Earlier this year, a team of investigators from the Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, both part of Northwestern University in Chicago, Illinois, published findings demonstrating a higher risk of metastatic recurrence among patients with EGFR-mutated tumors compared with those with wild-type EGFR.
The study, published in Oncotarget, retrospectively looked at 282 patients with early or locally advanced lung adenocarcinomas who had undergone definitive therapy. Tumor EGFR status was mutated in half of patients (n = 142) and wild type in the remainder. Whereas progression rates and progression-free survival (PFS) were similar between the groups, cases of disease recurrence were significantly more likely to be metastatic if the original tumor had an EGFR mutation (97% versus 68%).2
The investigators suggested possible reasons for the difference, including a theory that the EGFR-mutated phenotype is associated with unique tumor characteristics that lead to higher rates of microscopic foci, which go undetected and cause metastasis. A second hypothesis is that EGFR-mutated tumors have more “spillage” of cancer cells before or during surgery, eventually leading to higher rates of metastatic recurrence.
"This explanation is further supported by the overwhelming recurrence in lung parenchyma and pleura observed in the EGFR-mutated group, as these sites would be most affected by increased tumor cell burden in pulmonary veins,” the study authors wrote.
The evidence that EGFR mutations are associated with a significantly higher risk of later metastatic recurrence bolsters the case for increased molecular testing among patients with NSCLC, the authors argued.
If patients with EGFR-mutant NSCLC face a higher risk of metastatic recurrence, one challenge for investigators is to curb that risk. In June, Roy Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, unveiled the results of the phase 3 ADAURA trial (NCT02511106) examining the benefits of osimertinib (Tagrisso), a third-generation EGFR TKI, versus placebo in patients with EGFR-mutant stage IB to IIIA NSCLC following complete resection of the primary tumor.3
Patients in the study were randomized 1:1 to receive either oral osimertinib at 80 mg (n = 339) or placebo (n = 343) daily. Thirty-one percent of patients had stage IB cancer, and the remaining patients had stage II/IIIA cancer. Postoperative chemotherapy was allowed if indicated.
The results were striking. The 2-year disease- free survival (DFS) rate was 89% in patients who received osimertinib versus 53% in patients given placebo (HR, 0.21; 95% CI, 0.16-0.28; P < .0001). In the stage II/IIIA cohort, the 2-year DFS rate was 90% among osimertinib recipients compared with 44% in the placebo group (HR, 0.17; 95% CI, 0.12-0.23; P < .0001).
Liu noted that the trial was unblinded early due to the overwhelmingly positive nature of the efficacy data. He said a 30% reduction in the risk of relapse would have been impressive.
“Instead of showing a 30% reduction in risk, they really showed an 83% reduction in risk with a hazard ratio of 0.17 [for the patients with stage II/IIIA disease], which is a profoundly positive result showing that the benefit was much larger, perhaps, than initially expected,” Liu said.
The results demonstrate the strength of third-generation EGFR TKIs and suggest that early use of osimertinib in the adjuvant setting could lead to a dramatic reduction in the risk of recurrence among patients with EGFR-mutant NSCLC.
Osimertinib is currently FDA approved for the treatment of metastatic NSCLC in 2 settings: treatment-naïve patients with an EGFR exon 19 deletion or L858R point mutation and patients with an EGFR T790M point mutation whose disease progressed on prior EGFR TKI therapy.4
Although osimertinib has shown strong results in patients with early-stage disease, investigators are also probing for new ways to apply the drug to more metastatic setting indications. A recent open-label phase 1/2 trial (NCT02803203) evaluated pairing osimertinib with the VEGFR inhibitor bevacizumab (Avastin) for the treatment of metastatic EGFR-mutant lung cancer. The 49 patients on the trial were given 80 mg of osimertinib daily and bevacizumab at 15 mg/kg every 3 weeks.5
“It’s easy to forget it wasn’t that long ago that we didn’t really understand how these alterations impacted the treatment of cancer.”
The study showed a median PFS of 19 months, with a 12-month PFS rate of 76% (95% CI, 65%- 90%); the overall response rate was 80% (95% CI, 67%-91%). Of the 6 patients with central nervous system (CNS) disease, all had at least a partial CNS response to the therapy.5
Comparisons between the above phase 1/2 study and the earlier phase 3 FLAURA trial (NCT02296125) of osimertinib in patients with advanced EGFR-mutant NSCLC are revealing. Although both trials showed a median PFS of 19 months, the phase 1/2 study authors noted that the rate of brain metastases was higher in their trial. Moreover, the 100% CNS response rate among patients with CNS progression compared favorably with the 66% CNS response rate in the FLAURA study. FLAURA also had a larger proportion of patients with CNS progression (20% versus 10%); the results of the recent phase 1/2 trial suggest that the combination therapy may protect against CNS progression.5,6
One problem, however, is that earlier studies did not require baseline CNS surveillance imaging; such testing was required in the recent phase 1/2 study, whereas only 36% of patients in the FLAURA trial received it. Greater consistency and standardization of trial protocols in this regard would allow more robust comparisons of the benefits of the combination versus osimertinib alone.
Another combination of an EGFR TKI and a VEGFR inhibitor was evaluated in an interim analysis of the multicenter, open-label phase 3 NEJ026 trial, which compared erlotinib (Tarceva) at 150 mg per day as monotherapy versus combined with bevacizumab at 15 mg/kg every 3 weeks. The trial enrolled 228 patients with stage IIIB to IV or recurrent nonsquamous NSCLC with activating EGFR mutations. The team found a PFS of 16.9 months in the combination therapy group versus just 13.3 months in the erlotinib-only group (HR, 0.61, 95% CI, 0.42-0.88; P = .016).7
Five months later, in October 2019, findings of the phase 3 RELAY trial (NCT02411448), which compared the combination of erlotinib and the VEGFR2 inhibitor ramucirumab (Cyramza) versus erlotinib alone, were published in The Lancet Oncology. The 449 patients in the global study had untreated, EGFR-mutated, stage IV metastatic NSCLC. Patients received erlotinib at 150 mg daily plus 10 mg/kg ramucirumab or placebo every 2 weeks. Patients who received the combination had a PFS of 19.4 months versus 12.4 months in the group receiving erlotinib monotherapy (HR, 0.59; 95% CI, 0.46-0.76; P < .0001).8
The RELAY results served as the basis for the FDA approval of the combination as a first-line treatment for metastatic EGFR-mutated NSCLC.9
Lingering Questions and New Theories Though advances in treating and understanding EGFR-mutant NSCLC have been brisk, they have also raised a number of complicated issues, Liu said. One key question lingering over all of these new studies is the extent to which PFS benefit will translate into long-term improved overall survival (OS). This question can only be resolved with further research and more time.
Another question relates to TKI resistance. Though the first-generation TKIs gefitinib (Iressa) and erlotinib and the second-generation agents afatinib (Gilotrif) and dacomitinib (Vizimpro) have been effective, recurrence tied to acquired resistance has been a critical, ongoing problem. Osimertinib targets the most common resistance-related EGFR alteration, T790M, but there are already concerns about acquired resistance to this and other third-generation EGFR TKIs.10
Liu said investigators are exploring situations in which chemotherapy should be either paired with or replaced by EGFR TKIs. Whereas the latter agents have been able to replace chemotherapy for some patients, there is evidence that combining EGFR TKIs with chemotherapy can improve OS in patients with advanced EGFR-mutated NSCLC. For example, a 2019 report of findings from a phase 3 trial demonstrated a survival benefit from the addition of pemetrexed and carboplatin chemotherapy to gefitinib.11 However, the success of this strategy involving a first-generation EGFR TKI may not necessarily be repeated when newer drugs like osimertinib are combined with chemotherapy. Similar research is evaluating the benefits of combining TKIs with radiation therapy.
Liu said in the long term, he hopes clinicians will move away from a model relying on empiric observation and instead explore ways to devise personalized treatment strategies. Perhaps the most closely watched area for potential breakthroughs is immunotherapy. Liu said immunotherapy-based treatments have thus far produced stronger responses in lung cancers that are driven by a smoking history but have been less effective in oncogene-driven tumors, such as EGFR-mutant cancer. Still, he said some responses are being seen.
“If we can better understand how to elicit those responses, really capture those responses, that would be a major advance,” Liu said. “We’re in the early stages.”
More broadly, Liu said the fast pace of scientific advances will help clinicians progress beyond a one-size-fits-all approach to treating EGFR-mutant NSCLC. “Each cancer is unique,” he said. “Each patient is unique. And the more we can personalize these treatments to the problem at hand, the more effective our treatments are going to be in the long term.”
1. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta- analysis. Oncotarget. 2016;7(48):78985-78993. doi:10.18632/oncotarget. 12587
2. Galvez C, Jacob S, Finkelman BS, et al. The role of EGFR mutations in predicting recurrence in early and locally advanced lung adenocarcinoma following definitive therapy. Oncotarget. 2020;11(21):1953-1960. doi:10.18632/oncotarget.27602
3. Herbst RS, Tsuboi M, John T, et al: Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
4. Tagrisso. Prescribing information. AstraZeneca; 2015. Accessed July 9, 2020. https://bit.ly/2ZUJzdb
5. Yu HA, Schoenfeld AJ, Makhnin A, et al. Effect of osimertinib and bevacizumab on progression-free survival for patients with metastatic EGFR-mutant lung cancers: a phase 1/2 single-group open-label trial. JAMA Oncol. 2020;6(7):1048-1054. doi:10.1001/jamaoncol.2020.1260
6. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
7. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019;20(5):625-635. doi:10.1016/S1470-2045(19)30035-X
8. Nakagawa K, Garon EB, Seto T, et al; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5
9. Lilly’s Cyramza (ramucirumab) receives FDA approval as first-line treatment for metastatic EGFR-mutated non-small cell lung cancer. News release. Eli Lilly and Company. May 29, 2020. Accessed July 9, 2020. https://bit.ly/3iNlvSk
10. Nagano T, Tachihara M, Nishimura Y. Mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and a potential treatment strategy. Cells. 2018;7(11):212. doi:10.3390/cells7110212
11. Noronha V, Patil VM, Joshi A, et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J Clin Oncol. 2020;38(2):124-136. doi:10.1200/JCO.19.01154